Lenvatinib (Lenvima) is an orally available multi-kinase inhibitor that is used as a chemotherapeutic drug to treat cancers including thyroid, liver, renal, and endometrial cancers.

Lenvatinib (Lenvima)Uses:

• Advanced endometrial carcinoma:

  • Treatment of advanced endometrial carcinoma (in combination with pembrolizumab) that is not microsatellite instability-high or mismatch repair deficient, in patients who have disease progression following prior systemic therapy & who are not candidates for curative surgery or radiation.

• Unresectable hepatocellular carcinoma:

  • First-line treatment of unresectable hepatocellular carcinoma.

• Advanced renal cell carcinoma:

  • Treatment of advanced renal cell carcinoma (in combination with everolimus) following one prior anti-angiogenic therapy.

• Differentiated thyroid cancer:

  • Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

Lenvatinib (Lenvima) Dose in Adults:

Note:

• Lenvatinib is associated with a moderate emetic potential
• Antiemetics are recommended to prevent nausea and vomiting.

Lenvatinib (Lenvima) Dose in the Treatment of advanced endometrial carcinoma:

• Oral:
  • 20 mg OD (in combination with pembrolizumab)
  • Continue until disease progression or unacceptable toxicity.

Lenvatinib (Lenvima) Dose in the treatment of unresectable hepatocellular carcinoma:

• Oral:
  • 12 mg OD (patients ≥60 kg [actual body weight]) or 8 mg OD(patients <60 kg [actual body weight])
  • Continue until disease progression or unacceptable toxicity.

Lenvatinib (Lenvima) Dose in the Treatment of advanced renal cell carcinoma:

• Oral:
  • 18 mg OD (in combination with everolimus)
  • Continue until disease progression or unacceptable toxicity

Lenvatinib (Lenvima) Dose in the treatment of differentiated Thyroid cancer:

• Oral:
  • 24 mg OD until disease progression or unacceptable toxicity.

  • Missed doses:

    • Do not take a missed dose within 12 hours of the next dose (if within 12 hours, skip the missed dose and return to regular administration time).

Dosage adjustment for surgery:

• Temporarily interrupt lenvatinib for at least 6 days prior to scheduled surgery
• Resume therapy after surgery based on clinical judgment of adequate wound healing.

Use in Children:

Not indicated.

Lenvatinib (Lenvima) Pregnancy Risk Category: D

• Based on animal reproduction studies and the mechanism of action, lenvatinib could cause harm to fetuses if administered during pregnancy.
• Before initiating lenvatinib for females with reproductive potential, it is important to confirm your pregnancy status.
• Effective contraception should be used by females with reproductive potential during and for at least 30 day after treatment ends.

Use of Lenvatinib while breastfeeding

• It is unknown if lenvatinib secretes in breast milk.
• It is important to stop breastfeeding while receiving lenvatinib treatment. This will also be recommended for at least one week after the last dose.

Lenvatinib (Lenvima) Dose in Kidney Disease:

Note:

CrCl may be calculated by Cockcroft-Gault equation (using actual body weight).

• Preexisting renal impairment:

  • CrCl ≥30 mL/minute:

    • No dosage adjustment is necessary.

  • CrCl <30 mL/minute:

    • Advanced Endometrial carcinoma:
      • 10 mg OD.
    • Unresectable Hepatocellular carcinoma:
      • There are no dosage adjustments provided in the manufacturer's labeling.
    • Advanced Renal cell cancer:
      • 10 mg OD.
    • Differentiated Thyroid cancer:
      • 14 mg OD.

  • End-stage renal disease:

    • There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

  • Hemodialysis:

    • Lenvatinib is not expected to be dialyzable (due to high protein binding).

• Renal toxicity during treatment:

  • Nephrotic syndrome:

    • Permanently discontinue therapy.

  • Proteinuria ≥2 g proteinuria/24 hours:

    • Withhold therapy
    • Resume therapy at a reduced dose when improved to <2 g proteinuria/24 hours.

• Renal failure or impairment (grade 3 or 4):

  • Withhold therapy
  • If it improves to ≤ grade 1 or baseline, depending on the severity and persistence, resume at a reduced dose or permanently discontinue therapy.

Lenvatinib (Lenvima) Dose in Liver disease:

• Preexisting hepatic impairment:

  • Mild impairment (Child-Pugh class A):

    • No dosage adjustment is necessary.

  • Moderate impairment (Child-Pugh class B):

    • Advanced Endometrial carcinoma:
      • No dosage adjustment is necessary.
    • Unresectable Hepatocellular carcinoma:
      • There are no dosage adjustments provided in the manufacturer's labeling.
    • Advanced Renal cell cancer:
      • No dosage adjustment is necessary.
    • Differentiated Thyroid cancer:
      • No dosage adjustment is necessary.

  • Severe impairment (Child-Pugh class C):

    • Advanced Endometrial carcinoma:
      • 10 mg OD.
    • Unresectable Hepatocellular carcinoma:
      • There are no dosage adjustments provided in the manufacturer's labeling.
    • Advanced Renal cell cancer:
      • 10 mg OD.
    • Differentiated Thyroid cancer:
      • 14 mg OD.

  • Hepatotoxicity during treatment (grade 3 or 4):

    • Withhold therapy
    • If it improves to ≤ grade 1 or baseline, depending on the severity and persistence, resume at a reduced dose or permanently discontinue therapy.
    • Permanently discontinue for hepatic failure.

Common Side Effects of Lenvatinib (Lenvima):

• Cardiovascular:

  • Hypertension
  • Peripheral Edema

• Central Nervous System:

  • Fatigue
  • Headache
  • Voice Disorder
  • Mouth Pain
  • Dizziness
  • Insomnia

• Dermatologic:

  • Palmar-Plantar Erythrodysesthesia
  • Skin Rash
  • Alopecia

• Endocrine & Metabolic:

  • Increased Thyroid Stimulating Hormone Level
  • Weight Loss
  • Hypothyroidism
  • Increased Gamma-Glutamyl Transferase
  • Hyponatremia

• Gastrointestinal:

  • Diarrhea
  • Decreased Appetite
  • Nausea
  • Stomatitis
  • Vomiting
  • Abdominal Pain
  • Constipation
  • Dysgeusia
  • Xerostomia
  • Dyspepsia

• Genitourinary:

  • Proteinuria
  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Hemorrhage

• Hepatic:

  • Increased Serum Aspartate Aminotransferase

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia

• Renal:

  • Renal Insufficiency

• Respiratory:

  • Cough
  • Epistaxis

• Miscellaneous:

  • Fever

Less Common Side Effects of Lenvatinib (Lenvima):

• Cardiovascular:

  • Hypotension
  • Prolonged QT Interval On ECG
  • Cardiac Failure
  • Ventricular Dysfunction
  • Arterial Thromboembolism
  • Cardiac Abnormality
  • Pulmonary Embolism
  • Reduced Ejection Fraction

• Dermatologic:

  • Hyperkeratosis

• Endocrine & Metabolic:

  • Dehydration
  • Hypocalcemia
  • Hypokalemia
  • Hypercalcemia
  • Hypercholesterolemia
  • Hyperkalemia
  • Hypoalbuminemia
  • Hypoglycemia
  • Hypomagnesemia

• Gastrointestinal:

  • Infection Of Mouth
  • Increased Serum Lipase
  • Increased Serum Amylase
  • Gastrointestinal Fistula
  • Gastrointestinal Perforation

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Lymphocytopenia
  • Neutropenia
  • Anemia

• Hepatic:

  • Hepatic Encephalopathy
  • Hyperbilirubinemia
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase
  • Hepatic Failure

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Pulmonary Edema
  • Pneumonia

Contraindication to Lenvatinib (Lenvima):

• The US labeling of the manufacturer does not list any contraindications.

Canadian labeling

• Hypersensitivity to any component of the formulation or lenvatinib.

Warnings and precautions

• Cardiac effects

  • Patients treated with lenvatinib during clinical trials (including grades 3 and 4, which included hypertension) experienced hypertension frequently.
  • The median time it took for new or worsening hypertension to develop was between 16 and 35 days.
  • Hypertension that is not well controlled can lead to serious complications.
  • Monitor your blood pressure before you start therapy and continue to monitor it throughout the treatment.
  • Lenvatinib has been associated with serious (>= grade 3) and fatal cardiac dysfunction.
  • These include cardiomyopathy, left orright ventricular dysfunction, decreased left/right ejection fraction (>20% compared to baseline), heart failure or cardiac failure.
  • You should monitor for signs and symptoms of cardiac dysfunction.
  • Lenvatinib-treated people also experienced QT/QTc prolongation, with prolongations >500 msec and increases of >60 msec compared to baseline.
  • Electrolytes should be monitored (baseline and periodic) and corrected in all patients. Patients with congenital heart failure, congenital long QT syndrome, bradyarrhythmias or those taking concomitant medication known to prolong the QT interval, should have electrocardiograms.
  • Cardiac adverse reactions (hypertension, cardiac dysfunction, QT prolongation, or cardiac dysfunction) can require treatment interruption, dosage reduction or discontinuation.

• Fistula formulation/GI perforation

  • Lenvatinib has been associated with GI perforations and fistulas.
  • Patients who have GI perforation (any severity) and grade 3 or 4 fistula must be treated immediately.

• Toxicity to the gastrointestinal tract:

  • Lenvatinib has moderate emetic properties.
  • To prevent nausea and vomiting, antiemetics should be used.
  • Patients who have received lenvatinib have reported a lot of diarrhea. Grade 3 events were also common.
  • Combining everolimus with diarrhea was the most common cause of dose interruption or reduction. Diarrhea recurred even after dose reduction.
  • Diarrhea should be treated immediately.
  • Based on severity, discontinue lenvatinib. Upon recovery, you can resume lenvatinib at a reduced dosage or stop completely.

• Hemorrhage

  • Lenvatinib can cause serious and fatal hemorrhagic events.
  • Over 25% of patients who received lenvatinib as a single or combined agent with everolimus experienced hemorrhagic episodes (of any grade), with epistaxis, hematuria, and hematuria as the most commonly reported hemorrhagic symptoms.
  • A patient with CNS metastases at baseline was seen to have a fatal intracranial hemorrhage.
  • Patients who received lenvatinib along with everolimus, including rare fatal cases, were also reported to have suffered a cerebral hemorrhage.
  • Severe tumor-related bleeding events, including cases of fatal hemorrhage, have been reported.
  • Patients with anaplastic thyroid carcinoma (ATC), experienced more severe and fatal carotid hemorrhages than patients with other types of tumors.
  • ATC treatment with lenvatinib is not safe or effective.
  • Take into account the possibility of serious or fatal hemorrhage due to tumor infiltration/invasions of major blood vessels.
  • Monitor for bleeding. You may need to interrupt therapy, reduce dosage, or discontinue treatment permanently.

• Hepatotoxicity

  • Patients with other malignancies than hepatocellular carcinoma (HCC), who received lenvatinib, experienced serious hepatic adverse events. Fatal events, such as hepatic failure, acute liver disease, and hepatorenal symptoms, were also observed.
  • Patients with HCC treated with lenvatinib have reported hepatic complications, including encephalopathy and metabolic encephalopathy.
  • Monitoring the hepatic function of patients with HCC at baseline and during therapy is important. Also, monitor for signs of hepatic dysfunction such as encephalopathy or hepatic impairment.
  • Hepatotoxicity can require treatment interruption, dosage reduction, and/or discontinuation.
  • Patients with pre-existing hepatic impairment may need to reduce the initial dose.

• Hypocalcemia

  • Patients receiving lenvatinib have experienced hypocalcemia of grades 3-4. In most cases, the hypocalcemia was resolved or improved after calcium supplementation.
  • At least once a month, monitor serum calcium levels and replace calcium as needed.
  • Hypocalcemia can be treated with a combination of treatment interruptions, dosage reductions, and/or permanent discontinuation depending on its severity.

• Hypothyroidism

  • Exogenous thyroid suppression is impaired by Lenvatinib.
  • Patients with differentiated thyroid carcinoma (DTC), had a baseline level of thyroid-stimulating hormone(TSH) =0.5mil/L. However, patients with DTC who have a normal baseline TSH saw an increase of TSH >0.5mil/L.
  • Patients who received lenvatinib for another indication also experienced grade 1 or 2 hypothyroidism. Patients with normal or low TSH were often affected by an elevation in TSH.
  • Before starting lenvatinib, monitor your thyroid function at least monthly while you are receiving lenvatinib.
  • Follow the standard medical procedure to manage hypothyroidism.

• Palmar-plantar erythrodysesthesia

  • Nearly 1/3 of patients who received lenvatinib experienced palmar-plantar pain (usually grades 1 through 2).

• Toxicity in the renal system:

  • In clinical studies, proteinuria (including grade 3-toxicity) was often observed.
  • Monitor proteinuria at baseline and periodically during therapy.
  • If your urine dipstick for proteinuria >=2+, you can get a 24-hour urine sample.
  • You should not take any treatment for proteinuria greater than 2 g/24 hours. After recovery, you can resume your normal dose or stop taking it permanently (depending on how severe the condition).
  • Stop using the drug if you have nephrotic syndrome.
  • Severe renal impairment and/or failure can also occur (including >= Grade 3 events or fatal renal failure).
  • Dehydration and hypovolemia from diarrhea or vomiting are the main risk factors for renal impairment.
  • Start prompt management for diarrhea and dehydration/hypovolemia.
  • For grade 3 and 4 renal impairment or failure, withhold lenvatinib
  • Recommendations: Reduce the dose or stop taking it permanently depending on the severity and extent of your renal impairment/failure.
  • Patients with pre-existing renal impairment may need to reduce their initial dose.

• Reversible posterior Leukoencephalopathy Syndrome:

  • Rarely, a reversible posterior leukoencephalopathy (RPLS) has been observed.
  • MRI confirms that RPLS has been diagnosed.
  • Keep lenvatinib at bay; depending on severity and persistence, you may need to resume the medication or discontinue it completely.

• Events that are thromboembolic:

  • There have been reports of arterial thromboembolic episodes, including events >= grade 3.
  • If arterial thrombosis is detected, discontinue treatment immediately. It has not been proven safe to resume therapy.
  • Patients who have suffered an arterial thromboembolic event in the past 6 months are not eligible for Lenvatinib.

• Wound healing complications

  • Wound healing complications such as wound dehiscence and fistula formation can occur.
  • Keep lenvatinib at bay for at least 6 hours before your scheduled surgery
  • The clinical judgement and wound healing assessment should guide treatment for reinitiation.
  • Patients with wound healing problems should be permanently discontinued

Monitoring parameters:

• LFTs (at baseline, every 2 weeks for 2 months, and at least monthly thereafter)
• Renal function
• Electrolytes (baseline and periodically)
• Serum calcium at least monthly
• Thyroid function (TSH levels) at baseline and monthly or as clinically indicated
• Monitor for proteinuria at baseline and periodically during treatment (urine dipstick; if 2+ then 24-hour urine protein)
• Verify pregnancy status prior to treatment initiation (in females of reproductive potential).
• Monitor BP after 1 week, then every 2 weeks for 2 months, and at least monthly thereafter.
• ECG in select patients (congenital long QT syndrome, heart failure, bradyarrhythmias, or in those on concomitant medications known to prolong the QT interval)
• Monitor for clinical signs/symptoms of cardiac dysfunction, arterial thrombosis, reversible posterior leukoencephalopathy syndrome, fistula formation, GI perforation, bleeding/hemorrhagic events, diarrhea, dehydration, and wound healing complications
• Monitor patients with hepatocellular carcinoma closely for signs of hepatic failure, including hepatic encephalopathy.
• Monitor adherence.

How to administer Lenvatinib (Lenvima)?

• Lenvatinib is associated with a moderate emetic potential
• Antiemetics are recommended to prevent nausea and vomiting.

Oral:

• Administer orally at the same time each day.
• May be administered with or without food.
• Capsules may be swallowed whole or dissolved in a small glass of liquid.
• To dissolve in liquid, measure 15 mL of water or apple juice into a glass
• Add the whole capsule (do not break or crush the capsule) & leave it in liquid for at least 10 minutes, then stir for at least 3 minutes.
• Administer liquid, then add 15 mL of additional water or apple juice to the glass, swirl a few times, and then swallow the additional liquid.

Mechanism of action of Lenvatinib (Lenvima):

• Lenvatinib, a multitargeted inhibitor of vascular endothelial factor (VEGF), receptors VEGFR1(FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), and fibroblast growth factors (FGF), receptors FGFR1, 2, 3 and 4, platelet-derived factor receptor alpha (4PDGFRa), KIT and RET.
• These receptor tyrosine-kinases can be inhibited to reduce tumor growth and slow down the progression of cancer.
• Lenvatinib showed antiproliferative properties in hepatocellular carcinoma cells that were dependent on activated FGFR signals (with concurrent inhibition of FGF-receptor substrate 2, phosphorylation).
• Combining everolimus and lenvatinib has shown increased antiangiogenic activity. In vitro, it decreased human endothelial cell proliferation and tube formation, and VEGF signaling.

Absorption:

• Administration of a high-fat meal (900 Calories; 55% from fat, 15% from protein and 30% carbs) reduced the rate of absorption. However, it did not affect the amount of absorption.

Protein binding:

• 98% to 99%

Metabolism:

• Primarily enzymatic through CYP3A and aldehyde oxidase;
• nonenzymatic metabolism also occurs

Half-life elimination:

• ~28 hours

Time to peak:

• 1 to 4 hours

Excretion:

• Feces (~64%)
• urine (~25%)

International Brands of Lenvatinib (Lenvima):

• Lenvima (10 MG Daily Dose)
• Lenvima (12 MG Daily Dose)
• Lenvima (14 MG Daily Dose)
• Lenvima (18 MG Daily Dose)
• Lenvima (20 MG Daily Dose)
• Lenvima (24 MG Daily Dose)
• Lenvima (4 MG Daily Dose)
• Lenvima (8 MG Daily Dose)
• Kisplyx

Lenvatinib Brand Names in Pakistan:

No Brands are Available in Pakistan.

Lenvima is not a registered drug in Pakistan. However, patients may acquire it by writing a letter to the DRAP to make it available on a case-to-case basis (on a humanitarian basis). 

Since it is imported from nearby countries, the prices vary.